The present invention relates to porous, three dimensional structures for use in applications where a reduced foreign body capsule formation and increased adjacent vascularization is desired. Practical applications include membranes and coatings for devices to be implanted into animals.
Implantable medical devices with biological components are used for various purposes, such as indwelling chemical sensors, controlled drug-release systems, and biohybrid artificial organs for use with cellular therapies. See, for example, Colton, Implantable Biohybrid Artificial Organs, 4 Cell Transplant 415-36 (1995). All of these devices have in common the need for adequate perfusion of small and large molecules to or from the blood stream through the surrounding soft tissue. A serious problem in the development of devices for these applications is the formation of an avascular fibrous capsule around the implanted device. The capsule consists of (i) a layer of macrophages and/or foreign body giant cells at the material-tissue interface, overlain by (ii) an avascular region up to 100 xcexcm thick containing layers of fibroblasts embedded in a collagen matrix, which in turn is overlain by (iii) a region of blood vessels and fibroblasts in a loose connective tissue matrix. Spector, et al., The Local Tissue Response to Biomaterials, 5 Crit. Rev. Biocompat. 269-95 (1989). This capsule creates extra diffusion distance between the vasculature and the device. In addition, the tissue capsule may have inherently poor transport properties, as evidenced by measurements of glucose permeation through fibrotic tissue capsules formed on silicone rubber implanted subcutaneously in rats. The effective diffusion coefficient though this capsule is estimated to be one to two orders of magnitude lower than the value in water, Freeman, et al., A Study of the Mass Transport Resistance of Glucose Across Rat Capsular Membranes, 110 Mater. Res. Soc. Symp. Proc. 773-78 (1989). This reduced diffusion of nutrients and oxygen through the foreign body fibrous capsule has deleterious effects on the viability and/or function of tissues implanted in a biohybrid artificial organ.
Brauker discovered that certain microporous materials, when implanted subcutaneously, induce permanent neovascularization at the interface with host tissue by virtue of their morphology and microarchitecture. Brauker, et al., Neovascularization of Synthetic Membranes Directed by Membrane Microarchitecture, 29 J. Biomed. Mat. Res. 1517-24 (1995). This result was observed with membranes made from a variety of polymers using diverse fabrication methods, including solvent evaporation and stretching. The fact that this behavior was observed for membranes of widely varying chemical composition indicates that microarchitecture, rather than chemistry, is of primary importance in stimulating macrophage migration and neovascularization. Light microscopy revealed that the materials that induce neovascularization have interstices or openings that allow host inflammatory cells, such as monocytes and macrophages, to invade the membrane. Furthermore, once inside the membrane, many of these cells retain a non-flattened morphology and do not adhere to the very thin structural elements of the material. A fibrous capsule overlying the vasculature at the interface may also form around these materials. Brauker observed that materials that produce a thick fibrous capsule without neovascularization at the material-tissue interface had either interstices which were too small for host inflammatory cells to invade, or interstices which were large enough for virtually all of the host cells that invade the membrane to adhere and flatten on the internal structural elements of the material, which provided sufficiently large internal area for cell adhesion. Brauker generally found an increase in inflammatory cell penetration and an increase in vascular structures adjacent to the membrane when the nominal membrane pore size was about 1.0 xcexcm or larger.
Further, Padera demonstrated that the major events in the process of membrane microarchitecture-driven neovascularization occur within the first week of implantation. Padera, et al., Time Course of Membrane Microarchitecture-driven Neovascularization, 17 Biomaterials 277-84 (1996). Host inflammatory cells migrate into the membrane after three days of implantation. Their number increases for seven days, remains constant through 21 days and decreases by roughly half at 329 days. Blood vessels are found closer to the material-tissue interface with increasing time over the first week post-implantation. The vessels first arrive at the interface after three days, increasing rapidly through ten days, and then increase slowly through 21 days. The density of close vascular structures at the interface remained virtually constant after 21 days through 11 months, the duration of Padera""s experiment. Fibrous capsule formation starts as early as seven days post-implantation, and the capsule continues to mature until the fibroblasts die or migrate away to leave a nearly acellular, scar-like collagen matrix.
These results correlate with the course of events seen in normal wound healing. In normal wound healing, neutrophils are the predominant cell type at the site of injury within the first 24-48 hours, killing and phagocytosing any bacteria present. The macrophage becomes the predominant cell after this time, removing cellular and foreign debris from the area. Within three to four days, fibroblasts migrate out of the surrounding connective tissue into the wound area and begin to synthesize collagen, which quickly fills the wound space. New blood vessels begin to grow into the area at this time to supply oxygen and nutrients needed by the metabolically active fibroblasts and macrophages in the wound. An important difference between normal wound healing and membrane microarchitecture-driven neovascularization is that in normal wound healing the vessels begin to regress in the second week, but in membrane microarchitecture-driven neovascularization the vessels remain at the interface. Although the mature scar is avascular and acellular in a normal wound, in membrane microarchitecture-driven neovascularization, a multitude of vessels persist at the material-tissue interface in an otherwise largely acellular scar. This persistent adjacent vascular structure would be useful for maintaining the nutrient and oxygen supply to, and thus the viability of, the biological components of artificial organ devices.
These initial experiments which demonstrated the neovascularizing microarchitectural effect used membranes whose surface structure size and spacing were randomly generated, thereby producing an irregular structure. U.S. Pat. No. 5,807,406 describes a microfabricated porous laminar structure for holding living cells composed of net-like layers of polymer with regularly shaped holes. Although these structures are regular within the two dimensional plane of their laminar layers, they are irregular in the third dimensional plane. This creates a less well defined structure in which some interstices are blocked by strands of the polymer net from adjacent layers. Although these structures were also found to generally promote neovascularization at the structure/tissue interface upon implantation into animals, the xe2x80x9cblockedxe2x80x9d interstices did not allow invasion of those portions of the structure by inflammatory cells.
Although membranes and layered structures with completely or partially random geometries can exhibit neovascularizing properties, they tend to have areas on their surface comprising interstices which are too small or too large to promote neovascularization. It is desirable that the entire surface of the structure have interstices which allow the invasion of inflammatory cells and promote neovascularization adjacent to the implanted material. It has been discovered that microfabricated, grid-like, three dimensional porous structures are useful in implanted devices to promote adjacent neovascularization and reduce fibroid capsule thickness. The three dimensional porous structures of the invention have well defined, uniform geometries in three dimensions, with a microarchitecture that makes them particularly suitable for implanted device applications.
Among the several objects and features of the present invention may be noted the provision of a porous three dimensional structure suitable for use as a coating or membrane for use in various applications where a reduced thickness of the foreign body capsule and increased neovascularization are desired.
Briefly, apparatus of this invention is a porous three dimensional structure for implantation in a host animal capable of producing an inflammatory foreign body response. The structure comprises first and second layers spaced by a plurality of posts having a predetermined length connecting the first and second layers. Each of the layers has a plurality of openings of a predetermined size permitting fluids and inflammatory cells of the animal to pass through the openings and migrate into an interior volume defined by the first and second layers. The size of the openings and length of the posts promote a non-flattened morphology of the cells. The structure promotes vascularization adjacent to the structure when implanted into the animal.
In another aspect, the structure comprises first and second layers spaced by a spacer connecting the first and second layers. Each of the layers has a plurality of openings of a predetermined size permitting fluids and inflammatory cells of the animal to pass through the openings and migrate into an interior volume defined by the first and second layers. The size of the openings promotes a non-flattened morphology of the cells. The structure promotes vascularization adjacent to the structure when implanted in the animal. Each of the plurality of openings in the first layer is aligned with a corresponding opening of the plurality of openings in the second layer.
In yet another aspect, the invention is also drawn to devices for implantation into an animal which incorporate the three dimensional porous structure of the invention. These devices have at least one exterior surface which comprises the porous three dimensional structure.
In still another aspect, the porous three dimensional structure of the present invention comprises first and second layers spaced by a plurality of posts having a predetermined length connecting the first and second layers. Each of the layers has a plurality of openings of a predetermined size permitting fluids and inflammatory cells of the animal to pass through the openings and migrate into interior cavities defined by the openings in the layers and the posts. Each of the cavities has a volume adapted to promote a non-flattened morphology of the cells. The structure promotes vascularization adjacent to the structure when implanted into the animal.
Other objects and features of the present invention will be in part apparent and in part pointed out hereinafter.